The present invention relates to novel aryl-Z-alkoxy-5-benzylpyrimidines wherein Z is oxy, thio, imino, carbonyl, carbamoyl, sulfonyl, sulfinyl or sulfamoyl.
These compounds are potent inhibitors of dihydrofolate reductase (DHFR) which catalyzes the reduction of dihydrofolic acid to tetrahydrofolic acid (THFA), a widely used one-carbon carrier of metabolism. As a result, the novel compounds of this invention behave as folate antogonists and inhibit the growth of microorganisms by interfering with their reduction of dihydrofolic acid.
Conventionally, effective inhibition of microorganism growth has been achieved by the combined action of a benzyldiaminopyrimidine DHFR inhibitor such as trimethoprim (U.S. Pat. No. 3,049,544) and a sulfa drug including various derivatives of sulfanilamide which is thought to prevent dihydrofolate biosynthesis, (D. Lednicer and L. A. Mitscher, The Organic Chemistry of Drug Synthesis, John Wiley and Sons, New York, pp. 120-123, 1977). The combination of benzyldiaminopyrimidine and sulfa drug may exert their synergistic action through their ability to simultaneously inhibit DHFR. However, the combination therapy suffers from (1) allergic reactions due to sulfa drugs; and (2) problem of differing rates of metabolism and clearance of the components.
Accordingly it is an object of the present invention to provide novel phenyl-Z-alkoxy-5-benzylpyrimidines which encompass within one molecule a benzylpyrimidine moiety to block the MTX (methotrexate) site of DHFR; and an aryl-Z-alkoxy structure to block the adjacent "sulfa" site as well. The resulting "intramolecular" synergestic action is superior to that achieved by the combination therapy involving a benzylpyrimidine and a sulfa drug.
It is also an object of this invention to provide a new process for preparing the novel compounds of this invention.
A further object of this invention is to provide a novel method or utilizing these novel compounds as folate antagonists having antibacterial, anti-protozoal, and antitumor activities.
Still another object of this invention is to provide novel pharmaceutical compositions comprising one or more of the novel compounds of this invention as active ingredients.